Delivery of drug esters through an inhalation route

ABSTRACT

The present invention relates to the delivery of drug esters through an inhalation route. Specifically, it relates to aerosols containing drug esters that are used in inhalation therapy. In a method aspect of the present invention, a drug ester is delivered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises a drug ester, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% drug ester degradation product. In a kit aspect of the present invention, a kit for delivering a drug ester through an inhalation route is provided which comprises: a) a thin coating of a drug ester composition and b) a device for dispensing said thin coating as a condensation aerosol.

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/146,516 entitled “Delivery of Drug Esters Through anInhalation Route,” filed May 13, 2002, Rabinowitz and Zaffaroni, whichclaims priority to U.S. provisional application Ser. No. 60/294,203entitled “Thermal Vapor Delivery of Drugs,” filed May 24, 2001 and toU.S. provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, all of which are hereby incorporated byreference for all purposes.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of drug estersthrough an inhalation route. Specifically, it relates to aerosolscontaining drug esters that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

[0003] There are a number of compounds containing acids and alcoholsthat are currently marketed as drugs. In certain circumstances, thepresence of such functionality prevents effective drug delivery. Thisphenomenon could be due to a range of effects, including poor solubilityand inadequate transcellular transport.

[0004] It is desirable to provide a new route of administration for drugacids and alcohols that rapidly produces peak plasma concentrations ofthe compounds. The provision of such a route is an object of the presentinvention.

SUMMARY OF THE INVENTION

[0005] The present invention relates to the delivery of drug estersthrough an inhalation route. Specifically, it relates to aerosolscontaining drug esters that are used in inhalation therapy.

[0006] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of drugester. Preferably, the drug ester has a decomposition index less than 0.15. More preferably, it has a decomposition index less than 0.10 or0.05. Preferably, the particles comprise at least 10 percent by weightof drug ester. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or99.97 percent by weight of drug ester.

[0007] Typically, the drug ester is an ester of a drug from one of thefollowing classes: antibiotics, anticonvulsants, antidepressants,antihistamines, antiparkisonian drugs, drugs for migraine headaches,drugs for the treatment of alcoholism, muscle relaxants, anxiolytics,nonsteroidal anti-inflammatories, other analgesics and steroids.

[0008] Typically, where the drug ester is an ester of an antibiotic, itis selected from an ester of one of the following compounds:cefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile;cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin c;cephalotin; cephamycins, such as cephamycin a, cephamycin b, andcephamycin c; cepharin; cephradine; ampicillin; amoxicillin; hetacillin;carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin;benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin;nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin n,penicillin o, penicillin s, and penicillin v; chlorobutin penicillin;dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.

[0009] Typically, where the drug ester is an ester of an anticonvulsant,it is selected from an ester of one of the following compounds:4-amino-3-hydroxybutyric acid, ethanedisulfonate, gabapentin, andvigabatrin.

[0010] Typically, where the drug ester is an ester of an antidepressant,it is selected from an ester of one of the following compounds:tianeptine and S-adenosylmethionine.

[0011] Typically, where the drug ester is an ester of an antihistamine,it is an ester of fexofenadine.

[0012] Typically, where the drug ester is an ester of anantiparkinsonian drug, it is selected from an ester of one of thefollowing compounds: apomorphine, baclofen, levodopa, carbidopa, andthioctate.

[0013] Typically, where the drug ester is an ester of a drug formigraine headaches, it is selected from an ester of one of the followingcompounds: aspirin, diclofenac, naproxen, tolfenamic acid, andvalproate.

[0014] Typically, where the drug ester is an ester of a drug for thetreatment of alcoholism, it is an ester of acamprosate.

[0015] Typically, where the drug ester is an ester of a muscle relaxant,it is an ester of baclofen.

[0016] Typically, where the drug ester is an ester of an anxiolytic, itis selected from an ester of one of the following compounds:chlorazepate, calcium N-carboamoylaspartate and chloral betaine.

[0017] Typically, where the drug ester is an ester of a nonsteroidalanti-inflammatory, it is selected from an ester of one of the followingcompounds: aceclofenac, alclofenac, alminoprofen, amfenac, aspirin,benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate,carprofen, cinchophen, cinmetacin, clidanac, clopriac, clometacin,diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin,flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen,ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen,prodolic acid, salsalate, sulindac, tofenamate, and tolmetin.

[0018] Typically, where the drug ester is an ester of an otheranalgesic, it is selected from an ester of one of the followingcompounds: bumadizon, clometacin, and clonixin.

[0019] Typically, where the drug ester is an ester of a steroid, it isselected from an ester of one of the following compounds: betamethasone,chloroprednisone, clocortolone, cortisone, desonide, dexamethasone,desoximetasone, difluprednate, estradiol, fludrocortisone, flumethasone,flunisolide, fluocortolone, fluprednisolone, hydrocortisone,meprednisone, methylprednisolone, paramethasone, prednisolone,prednisone, pregnan-3-alpha-ol-20-one, testosterone, and triamcinolone.

[0020] Typically, where the drug ester is an ester of a drug acid, theester is selected from an ester of the following type: C₁-C₆ straightchain substituted or unsubstituted alkyl ester, C₁-C₆ branched chainsubstituted or unsubstituted alkyl ester, C₃-C₆ substituted orunsubstituted cyclic alkyl ester, C₁-C₆ substituted or unsubstitutedalkenyl ester, C₁-C₆ substituted or unsubstituted alkynyl ester, andsubstituted or unsubstituted aromatic ester.

[0021] Typically, where the drug ester is an ester of a drug alcohol,the ester is selected from an ester of the following type: C₁-C₆substituted or unsubstituted straight chain alkanoate, C₁-C₆ substitutedor unsubstituted branched chain alkanoate, C₁-C₆ substituted orunsubstituted alkenoate, and C₁-C₆ substituted or unsubstitutedalkynoate.

[0022] Typically, the drug ester is selected from one of the following:ketoprofen methyl ester, ketoprofen ethyl ester, ketoprofen norcholineester, ketorolac methyl ester, ketorolac ethyl ester, ketorolacnorcholine ester, indomethacin methyl ester, indomethacin ethyl ester,indomethacine norcholine ester, and apomorphine diacetate.

[0023] Typically, the aerosol has a mass of at least 0.01 mg.Preferably, the aerosol has a mass of at least 0.05 mg. More preferably,the aerosol has a mass of at least 0.10 mg, 0.15 mg, 0.2 g or 0.25 mg.

[0024] Typically, the particles comprise less than 10 percent by weightof drug ester degradation products. Preferably, the particles compriseless than 5 percent by weight of drug ester degradation products. Morepreferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03percent by weight of drug ester degradation products.

[0025] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0026] Typically, the aerosol has an inhalable aerosol drug ester massdensity of between 0.1 mg/L and 100 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 0.1 mg/L and 75 mg/L.More preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.1 mg/L and 50 mg/L.

[0027] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0028] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0029] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 2.Preferably, the geometric standard deviation is less than 1.9. Morepreferably, the geometric standard deviation is less than 1.8, 1.7, 1.6or 1.5.

[0030] Typically, the aerosol is formed by heating a compositioncontaining drug ester to form a vapor and subsequently allowing thevapor to condense into an aerosol.

[0031] In a method aspect of the present invention, a drug ester isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of drug ester, to form a vapor; and, b) allowing thevapor to cool, thereby forming a condensation aerosol comprisingparticles, which is inhaled by the mammal. Preferably, the drug esterhas a decomposition index less than 0. 15. More preferably, it has adecomposition index less than 0.10 or 0.05. Preferably, the compositionthat is heated comprises at least 10 percent by weight of drug ester.More preferably, the composition comprises at least 20 percent, 30percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percentor 99.97 percent by weight of drug ester.

[0032] Typically, the drug ester is an ester of a drug from one of thefollowing classes: antibiotics, anticonvulsants, antidepressants,antihistamines, antiparkisonian drugs, drugs for migraine headaches,drugs for the treatment of alcoholism, muscle relaxants, anxiolytics,nonsteroidal anti-inflammatories, other analgesics and steroids.

[0033] Typically, where the drug ester is an ester of an antibiotic, itis selected from an ester of one of the following compounds:cefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile;cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin c;cephalotin; cephamycins, such as cephamycin a, cephamycin b, andcephamycin c; cepharin; cephradine; ampicillin; amoxicillin; hetacillin;carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin;benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin;nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin n,penicillin o, penicillin s, and penicillin v; chlorobutin penicillin;dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.

[0034] Typically, where the drug ester is an ester of an anticonvulsant,it is selected from an ester of one of the following compounds:4-amino-3-hydroxybutyric acid, ethanedisulfonate, gabapentin, andvigabatrin.

[0035] Typically, where the drug ester is an ester of an antidepressant,it is selected from an ester of one of the following compounds:tianeptine and S-adenosylmethionine.

[0036] Typically, where the drug ester is an ester of an antihistamine,it is an ester of fexofenadine.

[0037] Typically, where the drug ester is an ester of anantiparkinsonian drug, it is selected from an ester of one of thefollowing compounds: apomorphine, baclofen, levodopa, carbidopa, andthioctate.

[0038] Typically, where the drug ester is an ester of a drug formigraine headaches, it is selected from an ester of one of the followingcompounds: aspirin, diclofenac, naproxen, tolfenamic acid, andvalproate.

[0039] Typically, where the drug ester is an ester of a drug for thetreatment of alcoholism, it is an ester of acamprosate.

[0040] Typically, where the drug ester is an ester of a muscle relaxant,it is an ester of baclofen.

[0041] Typically, where the drug ester is an ester of an anxiolytic, itis selected from an ester of one of the following compounds:chlorazepate, calcium N-carboamoylaspartate and chloral betaine.

[0042] Typically, where the drug ester is an ester of a nonsteroidalanti-inflammatory, it is selected from an ester of one of the followingcompounds: aceclofenac, alclofenac, alminoprofen, amfenac, aspirin,benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate,carprofen, cinchophen, cinmetacin, clidanac, clopriac, clometacin,diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin,flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen,ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen,prodolic acid, salsalate, sulindac, tofenamate, and tolmetin.

[0043] Typically, where the drug ester is an ester of an otheranalgesic, it is selected from an ester of one of the followingcompounds: bumadizon, clometacin, and clonixin.

[0044] Typically, where the drug ester is an ester of a steroid, it isselected from an ester of one of the following compounds: betamethasone,chloroprednisone, clocortolone, cortisone, desonide, dexamethasone,desoximetasone, difluprednate, estradiol, fludrocortisone, flumethasone,flunisolide, fluocortolone, fluprednisolone, hydrocortisone,meprednisone, methylprednisolone, paramethasone, prednisolone,prednisone, pregnan-3-alpha-ol-20-one, testosterone, and triamcinolone.

[0045] Typically, where the drug ester is an ester of a drug acid, theester is selected from an ester of the following type: C₁-C₆ straightchain substituted or unsubstituted alkyl ester, C₁-C₆ branched chainsubstituted or unsubstituted alkyl ester, C₃-C₆ substituted orunsubstituted cyclic alkyl ester, C₁-C₆ substituted or unsubstitutedalkenyl ester, C₁-C₆ substituted or unsubstituted alkynyl ester, andsubstituted or unsubstituted aromatic ester.

[0046] Typically, where the drug ester is an ester of a drug alcohol,the ester is selected from an ester of the following type: C₁-C₆substituted or unsubstituted straight chain alkanoate, C₁-C₆ substitutedor unsubstituted branched chain alkanoate, C₁-C₆ substituted orunsubstituted alkenoate, and C₁-C₆ substituted or unsubstitutedalkynoate.

[0047] Typically, the drug ester is selected from one of the following:ketoprofen methyl ester, ketoprofen ethyl ester, ketoprofen norcholineester, ketorolac methyl ester, ketorolac ethyl ester, ketorolacnorcholine ester, indomethacin methyl ester, indomethacin ethyl ester,indomethacine norcholine ester, and apomorphine diacetate.

[0048] Typically, the particles comprise at least 5 percent by weight ofdrug ester. Preferably, the particles comprise at least 10 percent byweight of drug ester. More preferably, the particles comprise at least20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent,80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5percent, 99.9 percent or 99.97 percent by weight of drug ester.

[0049] Typically, the condensation aerosol has a mass of at least 0.01mg. Preferably, the aerosol has a mass of at least 0.05 mg. Morepreferably, the aerosol has a mass of at least 0.10 mg, 0.15 mg, 0.2 gor 0.25 mg.

[0050] Typically, the particles comprise less than 10 percent by weightof drug ester degradation products. Preferably, the particles compriseless than 5 percent by weight of drug ester degradation products. Morepreferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent byweight of drug ester degradation products.

[0051] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0052] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0053] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 2.Preferably, the geometric standard deviation is less than 1.9. Morepreferably, the geometric standard deviation is less than 1.8, 1.7, 1.6or 1.5.

[0054] Typically, the delivered aerosol has an inhalable aerosol drugester mass density of between 0.1 mg/L and 100 mg/L. Preferably, theaerosol has an inhalable aerosol drug mass density of between 0.1 mg/Land 75 mg/L. More preferably, the aerosol has an inhalable aerosol drugmass density of between 0.1 mg/L and 50 mg/L.

[0055] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0056] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0057] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0058] Typically, between 0.1 mg and 100 mg of drug ester are deliveredto the mammal in a single inspiration. Preferably, between 0.1 mg and 75mg of drug ester are delivered to the mammal in a single inspiration.More preferably, between 0.1 mg and 50 mg of drug ester are delivered ina single inspiration.

[0059] Typically, the delivered condensation aerosol results in a peakplasma concentration of drug acid or drug alcohol in the mammal in lessthan 1 h. Preferably, the peak plasma concentration is reached in lessthan 0.5 h. More preferably, the peak plasma concentration is reached inless than 0.2, 0.1, 0.05, 0.02 or 0.01 h.

[0060] In a kit aspect of the present invention, a kit for delivering adrug ester through an inhalation route to a mammal is provided whichcomprises: a) a composition comprising at least 5 percent by weight ofdrug ester; and, b) a device that forms a drug ester aerosol from thecomposition, for inhalation by the mammal. Preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drugester.

[0061] Typically the drug ester has a decomposition index less than0.15. More preferably, it has a decomposition index less than 0.10 or0.05.

[0062] Typically, the device contained in the kit comprises: a) anelement for heating the drug ester composition to form a vapor; b) anelement allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

[0063]FIG. 1 shows a cross-sectional view of a device used to deliverdrug ester aerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0064] Definitions

[0065] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0066] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0067] “Aerosol drug ester mass density” refers to the mass of drugester per unit volume of aerosol.

[0068] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0069] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0070] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0071] “Decomposition index” refers to a number derived from an assaydescribed in Example 8. The number is determined by substracting thepercent purity of the generated aerosol from 1.

[0072] “Drug” refers to any chemical compound that is used in theprevention, diagnosis, treatment, or cure of disease, for the relief ofpain, or to control or improve any physiological or pathologicaldisorder in humans or animals. Such compounds are oftentimes listed inthe Physician's Desk Reference (Medical Economics Company, Inc. atMontvale, N.J., 56^(th) edition, 2002), which is herein incorporated byreference.

[0073] “Drug acid” refers to a drug containing a carboxylic acid moiety.

[0074] “Drug alcohol” refers to a drug containing a hydroxyl moiety.

[0075] “Drug Ester” refers to a drug acid or drug alcohol, where thecarboxylic acid group or hydroxyl group has been chemically modified toform an ester. The drug acids and alcohols from which the esters areformed come from a variety of drug classes, including, withoutlimitation, antibiotics, anticonvulsants, antidepressants,antihistamines, antiparkinsonian drugs, drugs for migraine headaches,drugs for the treatment of alcoholism, muscle relaxants, anxiolytics,nonsteroidal anti-inflammatories, other analgesics, and steroids.

[0076] Examples of antibiotics from which drug esters are formed includecefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile;cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin c;cephalotin; cephamycins, such as cephamycin a, cephamycin b, andcephamycin c; cepharin; cephradine; ampicillin; amoxicillin; hetacillin;carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin;benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin;nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin n,penicillin o, penicillin s, and penicillin v; chlorobutin penicillin;dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.

[0077] Examples of anticonvulsants from which drug esters are formedinclude 4-amino-3-hydroxybutyric acid, ethanedisulfonate, gabapentin,and vigabatrin.

[0078] Examples of antidepressants from which drug esters are formedinclude tianeptine and S-adenosylmethionine.

[0079] Examples of antihistamines from which drug esters are formedinclude fexofenadine.

[0080] Examples of antiparkinsonian drugs from which drug esters areformed include apomorphine, baclofen, levodopa, carbidopa, andthioctate.

[0081] Examples of anxiolytics from which drug esters are formed includechlorazepate, calcium N-carboamoylaspartate and chloral betaine.

[0082] Examples of drugs for migraine headache from which drug estersare formed include aspirin, diclofenac, naproxen, tolfenamic acid, andvalproate.

[0083] Examples of drugs for the treatment of alcoholism from which drugesters are formed include acamprosate.

[0084] Examples of muscle relaxants from which drug esters are formedinclude baclofen.

[0085] Examples of nonsteroidal anti-inflammatories from which drugesters are formed include aceclofenac, alclofenac, alminoprofen,amfenac, aspirin, benoxaprofen, bermoprofen, bromfenac, bufexamac,butibufen, bucloxate, carprofen, cinchophen, cinmetacin, clidanac,clopriac, clometacin, diclofenac, diflunisal, etodolac, fenclozate,fenoprofen, flutiazin, flurbiprofen, ibuprofen, ibufenac, indomethacin,indoprofen, ketoprofen, ketorolac, loxoprofen, meclofenamate, naproxen,oxaprozin, pirprofen, prodolic acid, salsalate, sulindac, tofenamate,and tolmetin.

[0086] Examples of other analgesics from which drug esters are formedinclude bumadizon, clometacin, and clonixin.

[0087] Examples of steroids from which drug esters are formed includebetamethasone, chloroprednisone, clocortolone, cortisone, desonide,dexamethasone, desoximetasone, difluprednate, estradiol,fludrocortisone, flumethasone, flunisolide, fluocortolone,fluprednisolone, hydrocortisone, meprednisone, methylprednisolone,paramethasone, prednisolone, prednisone, pregnan-3-alpha-ol-20-one,testosterone, and triamcinolone.

[0088] Examples of drug esters formed from drug acids include C₁-C₆straight chain substituted or unsubstituted alkyl esters, C₁-C₆ branchedchain substituted or unsubstituted alkyl esters, C₃-C₆ substituted orunsubstituted cyclic alkyl esters, C₁-C₆ substituted or unsubstitutedalkenyl esters, C₁-C₆ substituted or unsubstituted alkynyl esters, andsubstituted or unsubstituted aromatic esters. C₁-C₆ straight chainunsubstituted alkyl esters include, for example, methyl ester, ethylester and propyl ester. C₁-C₆ straight chain substituted alkyl estersinclude, for example, 2-(dimethylamino)-ethyl ester (—CH₂CH₂N(CH₃)₂).C₁-C₆ branched chain unsubstituted alkyl esters include, for example,isopropyl ester and isobutyl ester. C₁-C₆ branched chain substitutedalkyl esters include, for example, 2-(dimethylamino)-isopropyl ester(—CH(CH₃)CH₂N(CH₃)₂). C₃-C₆ unsubstituted cyclic alkyl esters include,for example, cyclopropyl and cyclohexyl ester. C₃-C₆ substituted cyclicalkyl esters include, for example, 2-(dimethylamino)-cyclopropyl ester.C₁-C₆ unsubstituted alkenyl esters include, for example, 2-butenyl ester(—CH₂CHCHCH₃). C₁-C₆ substituted alkenyl esters include, for example,4-(dimethylamino)-2-butenyl ester (—CH₂CHCHCH₂N(CH₃)₂). C₁-C₆unsubstituted alkynyl esters include, for example, 2-butynyl ester(—CH₂CCCH₃). C₁-C6 substituted alkynyl esters include, for example,4-(dimethylamino)-2-butynyl ester (—CH₂CCCH₂N(CH₃)₂). Unsubstitutedaromatic esters include, for example, phenyl ester and naphthyl ester.Substituted aromatic esters include, for example,4-(dimethylamino)phenyl ester.

[0089] Examples of drug esters formed from drug alcohols include C₁-C₆substituted or unsubstituted straight chain alkanoates, C₁-C₆substituted or unsubstituted branched chain alkanoates, C₁-C₆substituted or unsubstituted alkenoates, and C₁-C₆ substituted orunsubstituted alkynoates. C₁-C₆ unsubstituted straight chain alkanoatesinclude, for example, methanoate (—C(O)H), ethanoate (—C(O)CH₃) andpropanoate (—C(O)CH₂CH₃). C₁-C₆ substituted straight chain alkanoatesinclude, for example, 2-(phenyl)-ethanoate (—C(O)CH₂Ph). C₁-C₆unsubstituted branched chain alkanoates include, for example,isobutanoate (—C(O)CH(CH₃)₂). C₁-C₆ substituted branched chainalkanoates include, for example, 3-(phenyl)-isobutanoate(—C(O)CH(CH₃)CH₂Ph). C₁-C₆ unsubstituted alkenoates include, forexample, 2-butenoate (—C(O)CHCHCH₃). C₁-C₆ substituted alkenoatesinclude, for example, 4-(phenyl)-2-butenoate (—C(O)CHCHCH₂Ph). C₁-C₆unsubstituted alkynoates include, for example, 2-butynoate (—C(O)CCCH₃).C₁-C₆ substituted alkynoates include, for example,4-(phenyl)-2-butynoate.

[0090] Examples of other drug esters are found in U.S. Pat. No.5,607,691 to Hale et al. and U.S. Pat. No. 5,622,944 to Hale et al.These patents are herein incorporated by reference.

[0091] “Drug ester degradation product” refers to a compound resultingfrom a chemical modification of the drug ester. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0092] “Inhalable aerosol drug ester mass density” refers to the aerosoldrug ester mass density produced by an inhalation device and deliveredinto a typical patient tidal volume.

[0093] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0094] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0095] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0096] “Norcholine ester” refers to an ester where the portion attachedto the ester oxygen is —CH₂CH₂N(CH₃)₂.

[0097] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0098] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0099] “Rate of drug ester aerosol formation” refers to the mass ofaerosolized, drug ester produced by an inhalation device per unit time.

[0100] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0101] “Substituted” alkyl, alkenyl, alkynyl or aryl refers to thereplacement of one or more hydrogen atoms on the moiety (e.g., alkyl)with another group. Such groups include, without limitation, thefollowing: halo, amino, alkylamino, dialkylamino, hydroxyl, cyano, nitroand phenyl.

[0102] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0103] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0104] Formation of Drug Esters from Drug Acids or Drug Alcohols

[0105] Formation of drug esters from drug acids is typicallyaccomplished by reacting the acid, or an activated derivative (e.g.,acid chloride or mixed anhydride) with an appropriate alcohol underconditions well known to those of skill in the art. See, for example,Streitweiser, A., Jr. and Heathcock, C. H. (1981) Introduction toOrganic Chemistry, Macmillan Publishing Col., Inc., New York.Conversely, formation of drug esters from drug alcohols is typicallyaccomplished by reacting the alcohol with an appropriate activated acidderivative (e.g., ClC(O)CH₃). See Id.

[0106] Formation of Drug Ester Containing Aerosols

[0107] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising a drug ester to form a vapor, followed by cooling of thevapor such that it condenses to provide a drug ester comprising aerosol(condensation aerosol). The composition is heated in one of two forms:as pure active compound (i.e., pure drug ester); or, as a mixture ofactive compound and a pharmaceutically acceptable excipient.

[0108] Pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with drug ester. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

[0109] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0110] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of I cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0111] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yams and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0112] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yams and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0113] The heating of the drug ester compositions is performed using anysuitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic salvation, hydration of pyrophoric materials and oxidation ofcombustible materials.

[0114] Delivery of Drug Ester Containing Aerosols

[0115] Drug ester containing aerosols of the present invention aredelivered to a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating a drug ester containing composition to form a vapor; anelement allowing the vapor to cool, thereby providing a condensationaerosol; and, an element permitting the mammal to inhale the aerosol.Various suitable heating methods are described above. The element thatallows cooling is, in it simplest form, an inert passageway linking theheating means to the inhalation means. The element permitting inhalationis an aerosol exit portal that forms a connection between the coolingelement and the mammal's respiratory system.

[0116] One device used to deliver the drug ester containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a proximal end102 and a distal end 104, a heating module 106, a power source 108, anda mouthpiece 110. A drug ester composition is deposited on a surface 112of heating module 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module 106 (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element). The drug ester composition volatilizes due to theheating of heating module 106 and condenses to form a condensationaerosol prior to reaching the mouthpiece 110 at the proximal end of thedevice 102. Air flow traveling from the device distal end 104 to themouthpiece 110 carries the condensation aerosol to the mouthpiece 110,where it is inhaled by the mammal.

[0117] Devices, if desired, contain a variety of components tofacilitate the delivery of drug ester containing aerosols. For instance,the device may include any component known in the art to control thetiming of drug aerosolization relative to inhalation (e.g.,breath-actuation), to provide feedback to patients on the rate and/orvolume of inhalation, to prevent excessive use (i.e., “lock-out”feature), to prevent use by unauthorized individuals, and/or to recorddosing histories.

[0118] In Vivo Hydrolysis of Drug Esters

[0119] After delivery of a drug ester aerosol to the lung of an animal,the ester moiety is typically hydrolyzed to provide the correspondingdrug acid or drug alcohol, which produces a desired therapeutic effect.Where the ester reacts with water at ˜pH 7.4 at an appreciable rate,hydrolysis is chemically mediated. For other esters, hydrolysis isenzymatically mediated through the action of enzymes endogenous to theanimal.

[0120] Dosage of Drug Ester Containing Aerosols

[0121] A typical dosage of a drug ester aerosol is either administeredas a single inhalation or as a series of inhalations taken within anhour or less (dosage equals sum of inhaled amounts). Where the drugester is administered as a series of inhalations, a different amount maybe delivered in each inhalation. The dosage amount of drug ester inaerosol form is generally no greater than twice the standard dose of thedrug acid or drug alcohol given orally.

[0122] One can determine the appropriate dose of drug ester containingaerosols to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug acid or drugalcohol in an animal after its exposure to the aerosol. Mammals such asdogs or primates are typically used in such studies, since theirrespiratory systems are similar to that of a human. Initial dose levelsfor testing in humans is generally less than or equal to the dose in themammal model that resulted in plasma drug levels associated with atherapeutic effect in humans. Dose escalation in humans is thenperformed, until either an optimal therapeutic response is obtained or adose-limiting toxicity is encountered.

[0123] Analysis of Drug Ester Containing Aerosols

[0124] Purity of a drug ester containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

[0125] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0126] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of drug esterdegradation products.

[0127] Particle size distribution of a drug ester containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

[0128] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0129] Inhalable aerosol drug ester mass density is determined, forexample, by delivering a drug ester-containing aerosol into a confinedchamber via an inhalation device and measuring the amount ofnon-degraded drug ester collected in the chamber. Typically, the aerosolis drawn into the chamber by having a pressure gradient between thedevice and the chamber, wherein the chamber is at lower pressure thanthe device. The volume of the chamber should approximate the tidalvolume of an inhaling patient. The amount of non-degraded drug estercollected in the chamber is determined by extracting the chamber,conducting chromatographic analysis of the extract and comparing theresults of the chromatographic analysis to those of a standardcontaining known amounts of drug ester.

[0130] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug ester into a confined chamber via aninhalation device and measuring the number of particles of given sizecollected in the chamber. The number of particles of a given size may bedirectly measured based on the light-scattering properties of theparticles. Alternatively, the number of particles of a given size isdetermined by measuring the mass of particles within the given sizerange and calculating the number of particles based on the mass asfollows: Total number of particles=Sum (from size range 1 to size rangeN) of number of particles in each size range. Number of particles in agiven size range=Mass in the size range/Mass of a typical particle inthe size range. Mass of a typical particle in a given sizerange=π*D³*φ/6, where D is a typical particle diameter in the size range(generally, the mean boundary MMADs defining the size range) in microns,φ is the particle density (in g/mL) and mass is given in units ofpicograms (g⁻¹²).

[0131] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug ester into a confined chambervia an inhalation device. The delivery is for a set period of time(e.g., 3 s), and the number of particles of a given size collected inthe chamber is determined as outlined above. The rate of particleformation is equal to the number of I 00 nm to 5 micron particlescollected divided by the duration of the collection time.

[0132] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug ester into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the mass of particulate matter collected is determined by weighingthe confined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0133] Rate of drug ester aerosol formation is determined, for example,by delivering a drug ester containing aerosol into a confined chambervia an inhalation device over a set period of time (e.g., 3 s). Wherethe aerosol is pure drug ester, the amount of drug collected in thechamber is measured as described above. The rate of drug ester aerosolformation is equal to the amount of drug ester aerosol collected in thechamber divided by the duration of the collection time. Where the drugester containing aerosol comprises a pharmaceutically acceptableexcipient, multiplying the rate of aerosol formation by the percentageof drug ester in the aerosol provides the rate of drug aerosolformation.

[0134] Utility of Drug Ester Containing Aerosols

[0135] The drug ester containing aerosols of the present invention aretypically used for the same indication as the corresponding drug acid ordrug alcohol. For instance, a drug ester of baclofen would be used totreat parkinsons disease and a drug ester of fexofenadine would be usedto treat allergy symptoms.

[0136] The following examples are meant to illustrate, rather thanlimit, the present invention.

[0137] Drug acids or drug alcohols are typically commercially availablefrom Simga (www.sigma-aldrich.com), obtained in tablet form from apharmacy and extracted, or synthesized using well known methods in theart.

EXAMPLE 1 General Procedures for Esterifying a Drug Acid

[0138] Drug acid (10 mmol) is dissolved in 90 mL of dichloromethane. Tothe solution is added 1 drop of dimethylformamide and 13 mmol of oxalylchloride. The resulting mixture is allowed to stir 30 min. The mixtureis concentrated to dryness on a rotary evaporator to provide a residue,to which 50 mL of an alcohol (e.g., methanol) is added. The alcoholicsolution is concentrated to dryness to afford the desired drug ester.

[0139] Drug acid (6 mmol) is dissolved in 60 mL of dichloromethane. Tothe solution is added 1 drop of dimethylformamide and 9 mmol of oxalylchloride. The resulting mixture is allowed to stir 1 h. The mixture isconcentrated to dryness on a rotary evaporator to provide a residue, towhich 47 mmol of an alcohol (e.g., HOCH₂CH₂N(CH₃)₂) in 20 mLdichloromethane is added. The reaction mixture is diluted with 60 mLdichloromethane and subjected to a series of washings: 50 mL saturatedaqueous NaCl followed by 50 mL saturated aqueous NaHCO₃ and 2×50 mLsaturated aqueous NaCl. The dichloromethane extract is dried overNa₂SO₄, filtered, and concentrated on a rotary evaporator to provide thedesired drug ester.

EXAMPLE 2 General Procedure for Esterifying a Drug Alcohol

[0140] Drug alcohol (5 mmol) is dissolved in 50 mL of dichloromethane.To the solution is added 5.5 mmol Hünig's base and 10 mmol acetylchloride. The reaction mixture is allowed to stir at room temperaturefor 1 hour. The mixture is washed with 50 mL saturated aqueous NaHCO₃followed by 50 mL saturated aqueous NaCl. The dichloromethane extract isdried over Na₂SO₄, filtered, and concentrated on a rotary evaporator toprovide the desired drug ester.

EXAMPLE 3 Procedure for Diesterifying Apomorphine

[0141] Apomorphine-HCl/½H₂O (300 mg) was suspended in 600 μL of aceticacid. The suspension was heated to 100° C. and then cooled to 50° C.Acetyl chloride (1 mL) was added to the suspension, which was heated at40° C. for 3 h. The reaction mixture was allowed to cool to roomtemperature. Dichloromethane (1-2 mL) was added and the mixture wasallowed to stir overnight. The reaction mixture was diluted withdichloromethane, and the solvent was removed on a rotary evaporator.Toluene (10 mL) was added to the residue and subsequently removed on arotary evaporator. The toluene addition/removal was repeated. Theresulting solid residue was triturated with ether, providing 430 mg of asolid (mp 158-160° C.).

[0142] A portion of the solid (230 mg) was suspended in 50 mL ofdichloromethane. The suspension was washed with saturated aqueousNaHCO₃. The dichloromethane layer was dried over Na₂SO₄, filtered andconcentrated on a rotary evaporator to provide 190 mg of the desiredfree base (mp —110° C.).

EXAMPLE 4 Procedure for Synthesis of 2-(N,N-Dimethylamino)Ethyl Ester ofKetorolac

[0143] Ketorolac (255 mg), triethylamine (101 mg) and2-(dimethylamino)ethanol (HOCH₂CH₂N(CH₃)₂, 380 mg) were added to 2 mLdichloromethane. The mixture was cooled to −25° C. to −20° C. for 15min. BOP (464 mg) was added, and the reaction mixture was graduallyallowed to warm to room temperature. See Kim, M. H. and Patel, D. V.(1994) Tet. Lett. 35: 5603-5606. The reaction mixture was diluted with60 mL of dichloromethane and washed sequentially with saturated aqueousNaCl, saturated aquesous NaHCO₃ and then saturated aqueous NaCl. Thedichloromethane extract was dried over Na₂SO₄, filtered, andconcentrated on a rotary evaporator to provide 390 mg of the desiredmaterial.

EXAMPLE 5 General Procedure for Volatilizing Compounds from Halogen Bulb

[0144] A solution of drug in approximately 120 μL dichloromethane iscoated on a 3.5 cm×7.5 cm piece of aluminum foil (precleaned withacetone). The dichloromethane is allowed to evaporate. The coated foilis wrapped around a 300 watt halogen tube (Feit Electric Company, PicoRivera, Calif.), which is inserted into a glass tube sealed at one endwith a rubber stopper. Running 60 V of alternating current (driven byline power controlled by a variac) through the bulb for 5-12 s or 90 Vfor 2.5-3.5 s affords thermal vapor (including aerosol), which iscollected on the glass tube walls. (When desired, the system is flushedthrough with argon prior to volatilization.) Reverse-phase HPLC analysiswith detection by absorption of 225 nm light is used to determine thepurity of the aerosol.

[0145] Table 1, which follows, provides data from drugs volatilizedusing the above-recited general procedure. TABLE 1 AEROSOL AEROSOLCOMPOUND PURITY MASS Indomethacin Methyl Ester   99% 1.44 mgIndomethacin Ethyl Ester   >99% 3.09 mg Indomethacin Norcholine Ester  100% 2.94 mg Ketoprofen Methyl Ester   99%  4.4 mg Ketoprofen EthylEster 99.65% 4.11 mg Ketoprofen Norcholine Ester   100%  2.6 mgKetorolac Methyl Ester   100% 3.17 mg Ketorolac Ethyl Ester   >99% 5.19mg Ketorolac Norcholine Ester   100% 1.64 mg Apomorphine Diacetate-HCl  94% 1.65 mg Apomorphine Diacetate  96.9% 2.03 mg

EXAMPLE 6 General Procedure for Hydrolysis Studies of Drug Esters

[0146] Drug ester (20 μL, 10 mM acetonitrile) is added to 1 mL PBSsolution (pH 7.5) at room temperature. At intermittent time points, analiquot of the resulting mixture is injected into an HPLC to obtain theratio of drug ester to drug acid or drug alcohol. An Arrhenius plot ofthe data provides a t_(1/2) for hydrolysis. Table 2 below providest_(1/2) values for a variety of compounds. TABLE 2 COMPOUND t_(1/2)Ketoprofen Methyl Ester >48 h Ketoprofen Ethyl Ester >48 h KetoprofenNorcholine Ester 315 min. Ketorolac Methyl Ester >48 h Ketorolac EthylEster >48 h Ketorolac Norcholine Ester  14 min Indomethacin MethylEster >48 h Indomethacin Ethyl Ester >48 h Indomethacin Norcholine Ester315 min. Apomorphine Diacetate >48 h

EXAMPLE 7 General Procedure for Human Serum Hydrolysis Studies of DrugEsters

[0147] Human serum (2.34 mL) is placed in a test tube. To the serum isadded 260 μL of a 10 mM solution of drug ester in acetonitrile. The tubeis placed in a 37° C. incubator, and at various time points a 500 μLaliquot is removed. The aliquot is mixed with 500 μL methanol, and themixture is vortex mixed and centrifuged. A sample of the supernatant isanalyzed by HPLC obtain the ratio of drug ester to drug acid or drugalcohol. An Arrhenius plot of the data provides a t_(1/2) forhydrolysis. Table 3 below provides t_(1/2) values for a variety ofcompounds. TABLE 3 COMPOUND t_(1/2) Ketoprofen Methyl Ester  144 minKetoprofen Ethyl Ester  224 min Ketoprofen Norcholine   37 s EsterKetorolac Ethyl Ester   90 min Ketorolac Norcholine Ester   13 sIndomethacin Methyl Ester  >48 h Indomethacin Ethyl Ester  >48 hIndomethacin Norcholine   23 min Ester Apomorphine Diacetate 76.2 s

EXAMPLE 8 General Procedure for Screening Drug Esters for AerosolizationPreferability

[0148] Drug ester (1 mg) is dissolved or suspended in a minimal amountof a suitable solvent (e.g., dichloromethane or methanol). The solutionor suspension is pipeted onto the middle portion of a 3 cm by 3 cm pieceof aluminum foil. The coated foil is wrapped around the end of a 1½ cmdiameter vial and secured with parafilm. A hot plate is preheated toapproximately 300° C., and the vial is placed on it foil side down. Thevial is left on the hotplate for 10 s after volatilization ordecomposition has begun. After removal from the hotplate, the vial isallowed to cool to room temperature. The foil is removed, and the vialis extracted with dichloromethane followed by saturated aqueous NaHCO₃.The organic and aqueous extracts are shaken together, separated, and theorganic extract is dried over Na₂SO₄. An aliquot of the organic solutionis removed and injected into a reverse-phase HPLC with detection byabsorption of 225 nm light. A drug ester is preferred for aerosolizationwhere the purity of the drug ester aerosol isolated by this method isgreater than 85%. Such a drug ester has a decomposition index less than0.15. The decomposition index is arrived at by subtracting the percentpurity (i.e., 0.85) from 1.

1. A method of treating a disease or medical condition comprisingadministering a therapeutic amount of a drug ester condensation aerosol,having an MMAD less than 3 μm and less than 5% drug ester degradationproducts, to a patient by inhalation, upon activation by the patient ofthe formation of, and delivery of, the condensation aerosol.
 2. Themethod of claim 1, wherein said condensation aerosol is formed by a.volatilizing a drug ester under conditions effective to produce a heatedvapor of the drug ester; and b. condensing the heated vapor of drugester to form condensation aerosol particles.
 3. The method according toclaim 2, wherein said administration results in a peak plasmaconcentration of said drug ester in less than 0.1 hours.
 4. The methodof claim 2, wherein the drug ester is selected from the group consistingof: esters of antibiotics; esters of anticonvulsants; esters ofantidepressants; esters of antihistamines; esters of antiparkinsoniandrugs; esters of drugs for migraine headaches; esters of drugs for thetreatment of alcoholism; esters of muscle relaxants; esters ofanxiolytics; esters of nonsteroidal anti-inflammatories; esters of otheranalgesics; or esters of steroids.
 5. The method according to claim 3,wherein the administered aerosol is formed at a rate greater than 0.5mg/second.
 6. The method according to claim 1, wherein at least 50% byweight of the condensation aerosol is amorphous in form.
 7. A method oftreating a disease or medical condition comprising administering atherapeutic amount of an ester of an antibiotic; ester of ananticonvulsant; ester of an antidepressant; ester of an antihistamine;ester of an antiparkinsonian drug; ester of a drug for migraineheadaches; ester of a drug for the treatment of alcoholism; ester of amuscle relaxant; ester of an anxiolytic; ester of a nonsteroidalanti-inflammatory; ester of an other analgesic; or ester of a steroidcondensation aerosol, having an MMAD less than 3 μm and less than 5% ofan ester of an antibiotic; ester of an anticonvulsant; ester of anantidepressant; ester of an antihistamine; ester of an antiparkinsoniandrug; ester of a drug for migraine headaches; ester of a drug for thetreatment of alcoholism; ester of a muscle relaxant; ester of ananxiolytic; ester of a nonsteroidal anti-inflammatory; ester of an otheranalgesic; or ester of a steroid degradation products, to a patient byinhalation, upon activation by the patient of the formation of, anddelivery of, the condensation aerosol.
 8. The method of claim 7, whereinsaid condensation aerosol is formed by a. volatilizing an ester of anantibiotic; ester of an anticonvulsant; ester of an antidepressant;ester of an antihistamine; ester of an antiparkinsonian drug; ester of adrug for migraine headaches; ester of a drug for the treatment ofalcoholism; ester of a muscle relaxant; ester of an anxiolytic; ester ofa nonsteroidal anti-inflammatory; ester of an other analgesic; or esterof a steroid under conditions effective to produce a heated vapor of anester of an antibiotic; ester of an anticonvulsant; ester of anantidepressant; ester of an antihistamine; ester of an antiparkinsoniandrug; ester of a drug for migraine headaches; ester of a drug for thetreatment of alcoholism; ester of a muscle relaxant; ester of ananxiolytic; ester of a nonsteroidal anti-inflammatory; ester of an otheranalgesic; or ester of a steroid; and b. condensing the heated vapor ofan ester of an antibiotic; ester of an anticonvulsant; ester of anantidepressant; ester of an antihistamine; ester of an antiparkinsoniandrug; ester of a drug for migraine headaches; ester of a drug for thetreatment of alcoholism; ester of a muscle relaxant; ester of ananxiolytic; ester of a nonsteroidal anti-inflammatory; ester of an otheranalgesic; or ester of a steroid to form condensation aerosol particles.9. The method according to claim 7, wherein said administration resultsin a peak plasma concentration of an ester of an antibiotic; ester of ananticonvulsant; ester of an antidepressant; ester of an antihistamine;ester of an antiparkinsonian drug; ester of a drug for migraineheadaches; ester of a drug for the treatment of alcoholism; ester of amuscle relaxant; ester of an anxiolytic; ester of a nonsteroidalanti-inflammatory; ester of an other analgesic; or ester of a steroid inless than 0.1 hours.
 10. The method according to claim 7, wherein atleast 50% by weight of the condensation aerosol is amorphous in form.11. The method according to claim 7, wherein said ester of anantibiotic; ester of an anticonvulsant; ester of an antidepressant;ester of an antihistamine; ester of an antiparkinsonian drug; ester of adrug for migraine headaches; ester of a drug for the treatment ofalcoholism; ester of a muscle relaxant; ester of an anxiolytic; ester ofa nonsteroidal anti-inflammatory; ester of an other analgesic; or esterof a steroid condensation aerosol has an inhalable aerosol mass densityof between 0.1 mg/L and 100 mg/L when delivered.
 12. The methodaccording to claim 7, wherein the nonsteroidal anti-inflammatory isselected from a group consisting of ketoprofen, ketorolac, andindomethacin.
 13. The method according to claim 7, wherein theantiparkinsonian drug is apomorphine.
 14. The method according to claim7, wherein the ester is a methyl ester, an ethyl ester, or a norcholineester.
 15. The method according to claim 13, wherein the ester isapomorphine diacetate.
 16. A method of administering a drug ester to apatient to achieve a peak plasma drug concentration rapidly, comprisingadministering to the patient by inhalation an aerosol of a drug esterhaving less than 5% drug ester degradation products and an MMAD lessthan 3 microns wherein the peak plasma concentration of the drug esteris achieved in less than 0.1 hours.
 17. A method of administering anester of an antibiotic; ester of an anticonvulsant; ester of anantidepressant; ester of an antihistamine; ester of an antiparkinsoniandrug; ester of a drug for migraine headaches; ester of a drug for thetreatment of alcoholism; ester of a muscle relaxant; ester of ananxiolytic; ester of a nonsteroidal anti-inflammatory; ester of an otheranalgesic; or ester of a steroid to a patient to achieve a peak plasmadrug concentration rapidly, comprising administering to the patient byinhalation an aerosol of an ester of an antibiotic; ester of ananticonvulsant; ester of an antidepressant; ester of an antihistamine;ester of an antiparkinsonian drug; ester of a drug for migraineheadaches; ester of a drug for the treatment of alcoholism; ester of amuscle relaxant; ester of an anxiolytic; ester of a nonsteroidalanti-inflammatory; ester of an other analgesic; or ester of a steroidhaving less than 5% an ester of an antibiotic; ester of ananticonvulsant; ester of an antidepressant; ester of an antihistamine;ester of an antiparkinsonian drug; ester of a drug for migraineheadaches; ester of a drug for the treatment of alcoholism; ester of amuscle relaxant; ester of an anxiolytic; ester of a nonsteroidalanti-inflammatory; ester of an other analgesic; or ester of a steroiddegradation products and an MMAD less than 3 microns wherein the peakplasma drug concentration of an ester of an antibiotic; ester of ananticonvulsant; ester of an antidepressant; ester of an antihistamine;ester of an antiparkinsonian drug; ester of a drug for migraineheadaches; ester of a drug for the treatment of alcoholism; ester of amuscle relaxant; ester of an anxiolytic; ester of a nonsteroidalanti-inflammatory; ester of an other analgesic; or ester of a steroid isachieved in less than 0.1 hours.
 18. A kit for delivering a drug aerosolcomprising: a) a thin coating of a drug ester composition and b) adevice for dispensing said thin coating as a condensation aerosol. 19.The kit of claim 18, wherein the drug ester in the composition isselected from the group consisting of esters of antibiotics; esters ofanticonvulsants; esters of antidepressants; esters of antihistamines;esters of antiparkinsonian drugs; esters of drugs for migraineheadaches; esters of drugs for the treatment of alcoholism; esters ofmuscle relaxants; esters of anxiolytics; esters of nonsteroidalanti-inflammatories; esters of other analgesics; or esters of steroids.20. The kit of claim 18, wherein the device for dispensing said coatingof a drug ester composition as an aerosol comprises (a) a flow throughenclosure, (b) contained within the enclosure, a metal substrate with afoil-like surface and having a thin coating of a drug ester compositionformed on the substrate surface, (c) a power source that can beactivated to heat the substrate to a temperature effective to volatilizethe drug ester composition contained in said coating, and (d) inlet andexit portals through which air can be drawn through said device byinhalation, wherein heating the substrate by activation of the powersource is effective to form a drug ester vapor containing less than 5%drug ester degradation products, and drawing air through said chamber iseffective to condense the drug ester vapor to form aerosol particleswherein the aerosol has an MMAD of less than 3 microns.
 21. The kitaccording to claim 20, wherein the heat for heating the substrate isgenerated by an exothermic chemical reaction.
 22. The kit according toclaim 21, wherein said exothermic chemical reaction is oxidation ofcombustible materials.
 23. The kit according to claim 20, wherein theheat for heating the substrate is generated by passage of currentthrough an electrical resistance element.
 24. The kit according to claim20, wherein said substrate has a surface area dimensioned to accommodatea therapeutic dose of the drug ester composition in said coating. 25.The kit according to claim 18, wherein a peak plasma concentration ofdrug ester is obtained in less than 0.1 hours after delivery of thecondensation aerosol to the pulmonary system.
 26. The kit of claim 18,further including instructions for use.